Distinct clonal relationships among autoreactive IgG and IgA B-cells in pemphigus vulgaris. Homo sapiens

Lineage analysis of autoreactive B-cells can reveal the origins of autoimmunity. Inpemphigus vulgaris (PV), desmoglein 3 (DSG3) and DSG1 autoantibodies arepredominantly IgG4 and less frequently IgG1 and IgA, prompting us to investigatewhether anti-DSG IgG4 B cells are clonally related to IgG1, IgA1, and IgA2. Combiningsubclass-specific B-cell deep sequencing with high-throughput antibody screening, weidentified 80 DSG-reactive lineages from 4 PV patients. Phylogenetic analysisindicates anti-DSG IgA1-IgA2, IgG1-IgA1, IgG4-IgA2, and rarely, IgG1-IgG4 class-switch. Most anti-DSG IgG4 B-cells preferentially target DSG adhesion domains andlack inter-subclass clonal relationships, whereas anti-DSG IgA frequently evolve fromor to other subclasses and recognize a broader range of epitopes. Our findingssuggest that anti-DSG IgG4 B-cells predominantly evolve independently or divergeearly from other subclasses and that IgA is not the origin of most IgG autoreactivity inPV. These data provide novel insights into how autoreactivity develops and diversifiesacross B-cell subclasses.